3,7,9,11-tetramethyl-10-alkoxy or benzyloxytrideca - 2,7,11 - trienoic acids and esters containing a 4 position triple or double bond

ABSTRACT

NOVEL 3,7,9,11-TETRAMETHYL-10-METHOXY-TRIDECA-2,7,11TRIENOIC ACID ESTERS CONTAINING A TRIPLE OR DOUBLE BOND AT THE 4-POSITION WHICH ARE USEFUL AS INSECT HORMONAL AGENTS PREPARED FROM THE CONDENSATION PRODUCT OF TIGLIC ALDEHYDE WITH METHYL PROPENYL ETHER.

3,783,141 Patented Jan. 1, 1974 fUni cd Swe p (3mm 3,783,141 a a y t3,7,9,11-TETRAMETHYL-10-ALKOXY OR 5 BENZYL- OXYTRIDECA- 2,7,11 TRIENOICACIDS AND ESTERS CONTAINING A 4 POSITION TRIPLE OR DOUBLE BOND V jBeverly Ann Pawson, Montclair, and Gabriel Saucy, Essex Fells, N.J.,'assignors to Holfmann-La Roche -'Inc., Nutley, NJ. K r 1 No Drawing.Filed Dc. 17, 1971, Ser. No.-209,386r- Int. Cl. C07c 59/18,,69/66'; A01n9/24 US. Cl. 260-4103 R r t ABSTRACT. OF DISCLOSURE Novel 3,7,9,1 ltetramethyl-10 methoxy-trideca-2,7,1ltrienoic' acid esters containing atriple or do uble bond 16 Claims at the 4-position, which are useful asinsect hormonal gents preparedfrom the condensation product of tiglicaldehyde withmethylpropenyl ether,

acgordance. with t s invention, it has been found that compounds oftheformular R A wherein R is lower alkyl and R is lower alkyl or benzyl;

A and B individually are hydrogen or taken together form a carbon tocarbon bond;

are useful as insect hormonal agents and bactericides I 7 The compoundsof: Formula I are prepared, from the condensation productof a-compoundof the formula:

eme -CE.

wherein R is as-ab'oye;

wherein R is as above; via an intermediate of the formula:

CH CH CH3 .7 a (I-Ai wherein R, R and and are asabove, v a I On theother hand,"where the compound of. Formula l has the threo form, thecompound of Formula I has the following formula:

B cm wherein R, R A and B are as above.

The compounds of Formula LA and I-B can be in either the dor l-opticallyactive form or can be present as 'ar'acemic' mixture thereof.

Where the bond in the 4-position of the compound of Formula I is anolefinic double bond, the compound of bothFormulae I-A and 1-13 canexist in either the 4- trans form or in the 4-cis'form or as a mixturethereof. Also, the double bonds in the 2, 7 and ll-positions of thecompound of Formulae I, I-A or I-B can be either a cis double bond or atrans double bond or be a mixture of the 2, 7 and 11 cis and transisomers.

DETAILED DESCRIPTION The term lower alkyl as used throughout thisapplication comprehends both straight and branched chain hydrocarbongroups containing from 1 to 6 carbon atoms such as methyl, ethyl,propyl, isopropyl, etc. The term halogenr includes all four halogens,i.e., iodine, bromine, chlorine and fluorine with iodine, bromine andchlorin being preferred.

r The term ary as used throughout the application, includes mono-nucleararyl groups such as phenyl which can be unsubstituted or substituted inone or more positions with lower alkyl, halogen, lower alkoxy, amino,nitro, mono and dilower alkyl amino, etc., or polynuclear aryl groupssuch as naphthyl, anthryl, phenanthryl, azulyl, etc., which may besubstituted with one or more of the aforementioned groups. The preferredaryl radical is phenyl; The term -mono and dilower alkyl amino as usedthroughout the application, includes mono and dilower alkyl amino groupswherein the lower alkyl moieties contain from 1 to 6 carbon atoms suchas methyl, ethyl, isopropyl, etc. The term lower alkoxy comprehendslower alkoxy groups containing from 1 to 6 carbon atoms such as methoxy,propoxy, ethoxy, etc., preferably methoxy. The term lower alkylenedioxyas used throughout the specification, designates lower alkylenedioxygroups containing from 2 to 6 carbon atoms. Especially preferred are thealkylenedioxy groups such as ethylenedioxy. r 1 The numbering of thechain in the formulas given in this application is shown for the purposeof convenience.

In the structural formulas given throughout the application thesubstituents which are attached to the molecule above the plane of themolecule are designated by Y, and the substituents which are attached tothe molecule below the plane of the molecule are designated by E.

The erythro isomers which are set forth throughout this applicationdesignate those isomers which have the strucwherein R is a hydrocarbonresidue; and R is as above.

The threo isomers which are set'forth throughout this applicationdesignate the isomers which have the following structure:

CH H on, CHaCH=!g- :R'

wherein R and R are as above.

The compounds of Formula I are especially useful against insects,particularly linden bug. The compound of Formula I substantiallyinhibits adult formation of the linden bug at dosages of 10 meg/pupa andgreater.

: In contrast to most of the known pest-control agents which kill',dis'ab'le or repell the pestsby acting as contactpoisons andfeed-poisons, the compounds of Formula I 3 I 2 above prevent maturationan proliferationof by interfering with their hormonal system. Ininsects, for example, the transformation to the image, the laying ofviable eggs and the development of laid normal eggs is disturbed.Furthermore, the sequence of generations is interrupted and the insectsare indirectly killed. z

The compounds of Formula I above are particularly non-toxic tovertebrates. Moreover, these compounds are readily degraded and the riskof accumulation is therefore excluded. Therefore, these compounds can beused without fear or danger in the control of pests in animals; plants;foods; and textiles. I

Generally, in controlling invertebrate animals, the compounds of FormulaI are applied to the material. to be protected, e.g., foodstuffs, feeds,textiles, plants, in concentrations of from about 10- to 10- gm./cm. ofthe material to be protected. Generally, it is preferred to utilize thecompounds of Formula I above in a composition with a suitable inertcarrier. Any conventional inert carrier can be utilized.

. The compounds of Formula I can, for example, be used in the form ofemulsions, suspensions, dusting agents, solutions or aerosols. Inspecial cases, the materials to be protected (e.g., foodstuffs, feeds,textiles and the like) can alsobe directly impregnated with theappropriate compound or with a solution thereof. Moreover, the compounds.can also be used in a form which only releases them, by the action ofexternal influences (e.g., contact with moisture) or in the animal bodyitself. It is also possible to use the compounds in admixture with otherknown pesticides.

The compounds of Formula I above can be used as solutions suitable forspraying on the material to be protected which can be prepared bydissolving or dispersing these compounds in a solvent such as mineraloil fractions; cold tar oils; oils of vegetable or animal origins;hydrocarbons such as naphthalenes; ketones such as meth-' yl ethylketone; or chlorinated hydrocarbons such as tetrachloroethylene,tetrachlorobenzene, and the like. Such sprays suitably have aconcentration of the compound of Formula I of .01% to 5% by weight, witha concentration .1% being preferred. The compounds of Formulal above canalso be prepared in forms suitable for dilution with Water to formaqueous liquids such as, for example, emulsion concentrates, pastes orpowders. The compounds of Formula I above can be combined with solidcarriers for making, dusting or strewing powders as, for'example, talc,kaolin, bentonite, calcium carbonate, calcium phosphate, etc. Thecompositions containing the compoundsof Formula I above can contain, ifdesired, emulsifiers, dispersing agents, wetting agents, or other activesub-' stances such as fungicides, bactericides, nematocides, fertilizersand the like. The materials which are to' be protected act as bait forthe insect. In this manner, the insect,

condensation product of a compound of Formula II withv a compound ofFormula III. This condensation producthas the formula:

CH; CHa

wherein R is as above.

' The compound of Formula III is reacted withthe compound of Formula IIin the presence of an acid catalyst. In carrying out this reaction, anyof the conventional acid catalysts can be utilized. Among the preferredacid catalysts are included the Lewis acids such as zinc chloride,

aluminum chloride and boron trifluoride. Generally, this reaction iscarried out in an inert solvent. Any conventional inert organic solventcan be utilized for carrying out this reaction. Among the preferredinert organic solvents are included solvents such as ethyl acetate. Incarrying out this reaction, temperature and pressure are not criticaland this reaction can be carried out at room temperature and atmosphericpressure. Generally, it is preferredto utilize temperatures of from 0 C.to the reflux temperature of the reaction medium.

' If the double bond in the starting material of Formula H is a transdo'uble bond, the double bond at the 4-position inthe compoundof'Formula IV is. also atrans double bond. This transwconfiguration iscarried through the process so that the compound of Formula IIIA has a6-trans configuration and the compound of Formula I has an ll-transconfiguration. On the other hand, if the double bond' in the compound ofFormula II is a cis 7 double bond, the double bond at the 4-position ofthe compound of Formula IV is also a'cis double bond. This double bondis also carried through the entire'process so that'the compound ofFormula III-A has a 6-cis configuration and the compound of Formula Ihas an ll cis configuration. If the compound of Formula II is a mixtureof cis and trans isomers, the mixture is carried through the process sothat the compound of Formula-IV is a 4-cis/ trans mixture, ,the compoundof Formula III-A is a 6-cis and trans mixture and the compound ofFormula I isa ll-cis and trans mixture.

The acetals of Formula IV are selectively hydrolyzed by acid hydrolysisto produce an aldehyde of the formula:

. hydrofuran. Generally this selective hydrolysis is carried out attemperatures of from 0 10,60-1-10. L

y In the next stepof the process, the compound of Formula V is reactedwith a phosphorus ylide of the formula:

'/0 H3 s)3P=C-, 0

wherein R is as above; and R 'is aryl or dilower alkyl amino; to produce=the compound of'Formula III-A.

-Reaction between'the phosphorus ylide and the compound of Formula V toproduce the compound of Formula III-A'is carried out by heating thesereactants in aninert organic solvent. In carrying out 'thisreaction, anyconventional inert organic solvent can be utilized. Amongtheconventional inert organic solvents which can be utilized in accordancewith this invention are included aprotic solvents such as benzene,toluene, etc., or polar protic solvents such'as ethanol, methanol, etc.In carrying out 7 this reaction, reflux temperatures are generallyutilized.

The erythro isomer of the compound of Formula III-A liasthe formula:

IIHIIO wherein R is as above;

5. and the threo isomer of the compound of- Formtila'III-A has theformula: I

'cm n gm ens-o'- (III-All) wherein R is as above.

I solvent such as benzene is used, formation of the 2-trans isomer isfavored. Where a mixture of aprotic and polar protic solvents areutilized, a mixture of the 2-cis trans isomers of Formula III A occurs.Therefore, both the compound of Formula III-Ai and the compound ofFormula III-Aii can exist as 2-cis or 2-trans isomers or as a mixture ofthe 2-cis and 2-trans isomers.

Both the compoundof Formula III-Ai and the com pound of Formula III-Aiican also exist as optically active dor 1-isomers or can exist as aracemic mixture thereof.

The erythro and threo isomers of Formula III-'A (FormulaIII-Ai andFormula III-Aii) can be separated by conventional means, such as columnchromatography, vapor phase chromatography or fractional distillation.This separation can also take place with any of the intermediatesproduced in the conversion of the .compound of Formula III-A to thecompound of Formula I.

Both the erythro and threo isomers of the esters of Formula III-A canexist in the optically active dor l-forms or as a racemic mixture. Ifthe threo or erythro isomers exist as a racemic mixture, these racemicmixtures can be resolved by conventional procedures such as by reactingthe esters of Formula III-Ai or Formula III-Aii, after hydrolysisof theester to form the acid, with an optically active compound to afford amixture of optically active diastereomeric derivatives, separating thediastereomers by methods'known per se such as, for example,crystallization or chromatography and hydrolyzing the diastereomer toafford the desired enantiomer of the corresponding acid of the FormulaHI-Ai or Formula IlI-Aii. This optically active acid can be esterifiedto form the desired enantiomer of the ester of Formula lII-Ai or FormulaIII-Aii. Suitable optically active materials for preparing diastereomersof the compounds of the Formula III-Ai or Formula III-Aii are theoptically. active bases such as a-methylbenzylamine,u-methylnaphthylamine, quinine, morphine, etc. Any of the proceduresconventional in resolving compounds utilizing these bases can beutilized to resolve the compoundsof-the Formula III-Ai or FormulaIII-Aii. Also resolution can take place, if desired, with any of theintermediates produced in the conversion of the compound of the FormulaIII-A to the compound of the Formula I utilizing conventional resolutionprocedures.

The compound of Formula III-A which. can exist as a mixture of threo anderythro or in these isomeric forms, i.e., the compounds of FormulaeHI-Ai, or III-Aii, can be converted to the compound of Formula I where,if A and B are hydrogen, the double bond has a 4-cis configuration,i.e., a compound of the formula:

CH5 CH3 CH3 CH8 wherein R is a hydrolyzable hydroxy portecting group; Xis a halogen; A and B are as above; and R is as above.

The compound of Formula III-A is converted into a compound of Formula VII by treating the compound of Formula III-A with an alkali metalaluminum hydride or an aluminate reducing agent. Any of the conventionalalkali metal aluminum hydride or aluminate reducing agents can beutilized. Among the preferred alkali metal aluminum hydride reducingagents are included, lithium aluminum hydride, sodium aluminum hydride,etc. Among the preferred aluminate reducing agents are included sodiumdihydro-bis-(21methoxyethoxy)-aluminate. This reduction preferably iscarried out under anhydrous conditions in the presence of an inertorganic solvent. Any conventional inert organic solvent can be utilizedto carry out this reaction. Among the preferred inert organic solventsare included benzene, toluene, tetrahyrofuran, etc. In carrying out,this reaction, temperature and pressure are not critical and thereaction can be suitably carried out at room temperature or elevated orreduced temperatures. However, temperatures of from about -20 C. toabout 60 C. are generally preferred in carrying out this reaction.

The compound of Formula VII is converted to the compound of Formula VIIIabove, via reaction step (b), by subjecting the compound of Formula VIIto halogenation in the presence of a base. Any conventional method ofhalogenation can be utilized in carrying out the reaction step (b).Generally, the halogenation can be carried out by treating the compoundof Formula VII with a halogenating agent such as phosphorus tribromidein the presence of a base. Among the preferred bases are the tertiaryamines such as pyridine. In carrying out this reaction, any conventionalhalogenating agent and base can be utilized. This reaction is carriedout in the presence of a conventional inert organic solvent. Anyconventional inert organic solvent can be generally utilized. Among theconventional inert organic solvents are included diethyl ether,tetrahydrofuran, etc. In carrying out this reaction, temperature andpressure are not critical and this reaction can be carried out at roomtemperature and atmospheric pressure. If desired, temperatures of from50 C. to the reflux temperature of the reaction medium can be utilized.

The compound of Formula VIII is converted to the compound of Formula IX,via reaction step (c), by reacting the compound of Formula VIII with acompound of the formula:

wherein R is as above; and M is an alklali metal, preferably lithium oralkaline earth metal halide or a copper alkali metal complex thereof.

The compound of Formula IX is prepared by reacting the compound ofFormula VIII with the compound of Formula XXIV or a copper alkali metalcomplex thereof. If the compound of Formula DC is produced from thecompound of Formula XXIV, the compound of Formula XXIV and the compoundof Formula VIII are reacted in the presence of cuprous chloride.

The copper alkali metal complex is formed by reacting the compound ofFormula XXIV where M is an alkali metal with a cuprous halide. Thisreaction is carried out in an inert organic solvent. Any conventionalinert organic solvent can be utilized in this reaction with the ethersolvents such as diethyl ether, tetrahydrofuran being preferred. Incarrying out this reaction temperatures of from C. to 100 C. can beutilized.

In carrying out the reaction with either the compound of Formula XXIV ora copper alkali metal complex thereof, an inert organic solvent can beutilized as the reaction medium. Any conventional inert organic solventcan be utilized for this purpose. Among the conventional inert organicsolvents are included the ether solvents such as diethyl ether,tetrahydrofuran, etc. In carrying out this reaction, temperature andpressure are not critical and this reaction can be carried out at roomtemperature and atmospheric pressure. On the other hand, higher or lowertemperatures can be utilized. Generally, temperatures of from -80 C. to100 C. can be utilized in carrying out this reaction. The reaction ofthe compound of Formula VIII with the acetylide of Formula XXIV producesthe compound of Formula IX having the same configuration at the2-position as the configuration of the double bond in the acetylide ofFormula XXIV. If the double bond in the acetylide has a transconfiguration, the double bond at the 2-position in the compound ofFormula IX will also have a trans configuration and the configurationwill remain the same throughout its conversion into compounds of theFormulae X, XI, XII and VI. If the double bond in the acetylide has acis configuration, the double bond at the 2-position of the compound ofFormula IX will also have a cis configuration. This 2-cis configurationwill remain the same throughout its conversion into compounds of theFormulae X, XI, XII and VI. On the other hand, if the acetylide is amixture of isomers having a cis and trans configuration about the doublebond, the compound of Formula IX will also be a mixture of isomershaving a Z-cis and 2-trans configuration. If this mixture is convertedto the compound of Formula VI,

8 the intermediates of Formulae X, )H and XII will all be mixtures ofthe 2-cis and trans isomers.

In the compound of Formula IX and in the alkali metal acetylide ofFormula XXIV, R, can be a hydrolyzable ether group. These etherifiedhydroxy groups on conventional ether hydrolysis produce the hydroxymoiety. Suitable ether protecting groups are, tetrahydropyranyl ether,aryl methyl ethers, such as benzyl, benzhydryl, and trityl ethers ora-lower alkoxy lower alkyl ethers or methoxy methyl ethers or allylicethers such as allyl ether.

If desired, the compound of Formula IX can be catalytically hydrogenatedto produce the compound of Formula IX where A and B' are hydrogen. Thishydrogenation is carried out in an inert organic solvent such as ethylacetate, toluene or petroleum ether in the presence of a selectivehydrogenation catalyst, e.g., a palladium lead catalyst in the presenceof quinoline [disclosed in Helvetica Chimica Acta 35, 446 (1952)]. Theuse of a selective hydrogenation catalyst converts the triple bond inthe compound of Formula IX to a double bond at the 4-position which hasa cis configuration.

The conversion of a compound of the Formula IX to a compound of theFormula X can take place by conventional ether hydrolysis.

The compound of Formula X is converted to the aldehyde of Formula XI bymeans of oxidation as in step (c). Any oxidizing agent which willoxidize a hydroxy group to an aldehyde group can be utilized in carryingout this step. Among the preferred oxidizing agents are includedmanganese dioxide. The compound of Formula XI can be oxidized to thecompound of Formula XII via step (t) by treating the compound of FormulaXI with an oxidizing agent. Any conventional oxidizing agent which canbe utilized to oxidize aldehydes to the corresponding carboxylic acidscan be utilized in carrying out this reaction. Among the preferredoxidizing agents for use in this reaction is silver oxide or silvernitrate. Generally, this reaction can be carried out in the presence ofan inert organic solvent. Any conventional inert organic solvent can beutilized in carrying out this reaction. Typical inert organic solventswhich can be utilized include benzene, hexane, ethanol, etc. The use ofthe inert solvents will depend to a large extent on the oxidizing agentused. The oxidation reaction, can, if desired, be carried out in thepresence of an inorganic acid or alkali depending upon the choice of theoxidizing agent. In carrying out this oxidation reaction, temperatureand pressure are not critical and this reaction can be carried out atroom temperature and atmospheric pressure. Generally, it is preferred toutilize a temperature of from 0 C. to about 50 C.

On the other hand, the compound of Formula X can be directly oxidized toa compound of the Formula XII. In carrying out this reaction, anyoxidizing agent which will directly oxidize alcohols to thecorresponding carboxylic acid can be utilized. Among the preferredoxidizing agents are silver nitrate or silver oxide. Generally, thisreaction is carried out in the solvent medium. Any conventional inertorganic or inorganic solvent such as water, acetone, hexane, etc., canbe utilized. The oxidation reaction can be carried out at roomtemperature if desired. However, higher or lower temperatures can beutilized. Generally, it is preferred to utilize a temperature of from 10C. to C.

The compound of Formula XII can be converted to the compound of FormulaVI by esterification. Any conventional means of esterification can beutilized to carry out this reaction. Typical esterifying agents whichcan be utilized include diazo lower alkanes, such as diazo methane,diazo ethane; lower alkanols such as methanol, ethanol, isopropanol orlower alkyl halides such as methyl iodide, etc. Generally, this reactiontakes place either in the presence of an acid or base. Any conventionalinorganic acid or base can be utilized in conjunction with theaforementioned esterifying agent. Among the inorganic bases which can beutilized .in accordance with this invention are sodium hydroxide,potassium carbonate, pyridine,fsodium methoxide, etc. The choice ofaparticular base or acid depends on the particular esterifyingl agentused. Incases where lower alkanols are the esterifying agents, thereaction is generally carried out in the presence of an acid such assulfuric or hydrochloric .acid. General- Iyit is preferred to carryoutthis. esterification reaction in the presence of an inert organicsolvent. Any conventional inert organic solvent canbe utilized incarrying out this reaction. Among the preferred inert organic sol,-vents which can be utilized are included diethyl ether, petroleum ether,methyl ether, etc. In carrying out this reaction, temperature andpressure are not'critical. Therefore, this reaction can be carried outat room temperature and atmospheric pressure or' at elevatedtemperatures and pressures. Generally, it is preferred to carry out thisreaction at a temperature of from C. to the boiling point of thesolvent.

Where A and B in the compound of Formula I form a double bond having atrans configuration, this compound can be prepared from the compound ofFormula VIII by the following reaction scheme:

wherein R and R are as above; and R5 .is-a hydrolyzable 10 A ketalpand Aindicates that the double bond has a transconfiguration. i In convertingthe compound of Formula VIII above to the compound .of Formula XV above,the compound of Formula VIII is reacted with an acetylide of theformula:

wherein M and R are as above.

or copper alkali metal complex thereof.

Inthe compound of Formula XXV, R can be any conventional hydrolyzableketal group. These hydrolyzable ketal'groups can be hydrolyzed toregenerate the ketone. Among the preferred hydrolyzable ketoneprotecting groups are included lower alkylene dioxy which are formed'byreacting the 0x0 group of the ketone with a lower alkanediol. M, in thecompound of Formula XXV, can be any alkali metal, preferably lithium, oralkaline earth metal halide.

In preparing the compound of Formula XV above, the compound of FormulaVIII can be in its threo or erythro form or can be a mixture thereof.Separation of the mixtures can, if desired, be carried out at any stageof the process for converting the compound of Formula VIII to thecompound of Formula XXI. Any conventional means of separation can beutilized such as those hereinbefore mentioned. The preferred means ofseparat ing these isomers is by chromatography of silica gel. Also, thethreo or erythro isomers can be either in their optically active d or 1form or be a racemic mixture thereof. If the threo or erythro isomersare racemic mixture, this racemic mixture can be separated byconventional methods such as mentioned hereinbefore. Also separation ofthe racemic mixtures can, if desired, be carried out at any stage of theprocess for converting the compound of Formula VII to the compound ofFormula XXI.

The reaction of the compounds of the Formula VIII with the compounds ofthe Formula XXV is carried out under the same reaction conditionsdescribed hereinbefore in connection with the reaction of the acetylideof Formula XXIV with the compound of Formula VIII to produce thecompound of Formula IX. The compound of Formula XV is converted to thecompound of the Formula XVI by conventional acid hydrolysis. Anyconventional. means for hydrolyzing a ketal group to the correspondingketone can be utilized in carrying out this reaction. The compound ofFormula XVI is converted to the compound of Formula XVII via reactionstep (j), by treating the compound of the Formula XVI with an alkalimetal complex hydride reducing agent, preferably lithium aluminumhydride. In carrying out this reaction, any of the conditionsconventional for reducing with an alkali metal aluminum hydride can beutilized. Generally, it is preferred to carry out this reaction in thepresence of an organic solvent. The preferred inert organic solvents arethe ether solvents such as tetrahydrofuran. In carrying out thisreaction, temperatures from" l0 C. to the reflux temperature ofthe-reaction medium can be utilized. Reduction of the compound ofFormula XVI with an alkali metal aluminum hydride produces a transdouble bond at the 2-position of the compound of Formula XVII.

The compound of Formula XVII is converted to the compound of'the FormulaXVIII, via reaction step (k), by treating the compound of Formula XVIIwith an oxidizing agent-Any conventional oxidizing agent which willoxidize an alcohol to a ketone can be utilized in carrying out thisreaction. The preferred oxidizing agent for use in this reaction ismanganese dioxide. The reaction step (k). can take place utilizing thesame conditions described in connection with the conversion of acompound of Formula X to a, compound of the Formula XI via reaction step(e).

The conversion of the compound of the Formula XVIII to a compound of theFormula XD( can take place, via reaction step (l), by reacting thecompound of the For mula XVIII with a compound of the formula:

wherein R is aryl, aryloxy or lower alkoxy.

The reaction between the compound of Formula XVIII and the compound ofthe Formula XXX is carried out in the presence of an alkali metal basein an inert solvent medium. Any conventional alkali metal base can beutilized. Among the conventional alkali metal bases are included alkalimetal hydrides such as sodium hydride, potassium hydride; and the alkalimetal amide bases such as so damide, potassium amide, sodiummethylamide, potassium methylamide as well as other alkali metal alkylamides. In carrying out this reaction, any conventional inert organicsolvent can be utilized such as benzene, toluene, N,N-dimethylformamide,tetrahydrofuran, dioxane and 1,2-dimethoxyethane. In carrying out thisreaction, temperatures of from C. to 35 C. should be utilized.

The aldehyde of Formula XIX is converted to the acid of Formula XX viareaction step (In) in the same manner as described in connection withthe oxidation of a compound of the Formula XI to a compound of theFormula XII, via reaction step (f). The compound of Formula XX is thenesterified by the procedure given in reaction step (g) for theesterification of the compound of the Formula XII to the compound of theFormula VI. The esterification of the compound of the Formula XXproduces the compound of the Formula XXI.

In accordance with another embodiment of this invention, the compound ofFormula XVIII can be directly converted to the compound of the FormulaXXI by reacting the compound of the Formula XVIII with a compound of theformula:

(XXX) O (XXXVI) wherein R and R are as above.

This reaction is carried out by utilizing the same procedure that wasutilized to react a compound of the Formula XVIII with a compound of theFormula XXX as in step (1). Generally it is preferred to carry out thereaction in the presence of a base such as an alkali metal loweralkoxide.

The following examples are illustrative but not limitative of thisinvention. The ether utilized in these examples was diethyl ether. Thetemperature in all of the following examples is in degrees centigrade.

EXAMPLE 1 Cisand trans-methyl propenyl ether A 2.5-cm. diameter glasscolumn, 51 cm. overall length of which 35 cm. was packed with 4-8 meshpumice stone, was encased in a Lindberg Hevi Duty pyrolysis oven. Adropping funnel was attached at the top of the column and the bottom ofthe column was attached to a receiver 'cooled in Dry Ice acetone. Theglass column was heated to 325 C. Propionaldehyde dimethyl acetal (117.0g.) was added dropwise under nitrogen at the top of the column; amixture of starting acetal, methyl propenyl ether and methanol wascollected in the receiver. This mixture was washed with a 5% by weightaqueous sodium carbonate solution, dried with anhydrous potassiumcarbonate and finally distilled at 40-50 C. to give a 1:1 part by weightmixture of cisand trans-methyl propenyl ether.

1 2 EXAMPLE 2 Tiglic aldehyde dimethyl acetal (52.0 g.), and 10 ml. of a10% by weight solution of zinc chloride in ethyl acetate were placed ina 250 ml. flask equipped with a magnetic stirrer and dropping funnel.The reaction was conducted in an atmosphere of nitrogen. The mixture washeated to 40-45" C., and 31.7 g. of methyl propenyl ether was added overa 30-minute period. After the addition was complete, the reactionmixture was stirred at 40-45 C. overnight. The mixture was diluted withdiethyl ether, washed successively with dilute aqueous sodium hydroxideand saturated aqueous sodium chloride solution, and finally dried withsodium sulfate. Evaporation of the solvent and distillation of theresidue alforded 2,4-dimethyl- 3-methoxy-4-hexenal dimethyl acetal, B.P.-95 C. (10 mm. Hg).

EXAMPLE 3 The acetal was hydrolyzed with a 2:1 parts by volume solutionof 5% by weight aqueous sulfuric acid solution in tetrahydrofuran atroom temperature to give after extraction2,4-dimethyl-3-meth0xy-4-hexenal.

EXAMPLE 4 18 g. (0.05 mole) of carbethoxyethylidenetriphenylphosphorane, 7.8 g. (0.05 mole) of2,4-dimethyl-3-methoxy-4-hexenal and ml. of dry benzene were heated toreflux for 48 hours in an inert atmosphere. The reaction mixture wasallowed to cool and was poured into ice Water. The organic phase wasseparated and the aqueous phase was extracted twice with diethyl ether.The combined organic phase was washed with saturated aqueous sodiumchloride solution and dried with anhydrous sodium sulfate. Evaporationof the solvent gave a yellow solid which was triturated three times withpentane. Removal of the pentane afforded a mixture consisting ofd,l-erythro-trans,trans-2,4,6 trimethyl-5-methoxyocta-2,6- dienoic acidethyl ester andd,l-threo-trans,trans-2,4,6-trimethyl-S-methoxyocta-Z,6-dienoic acidethyl ester.

EXAMPLE 5 The mixture obtained in Example 4 was purified bychromatography on silica gel (ratio 30:1) and elution with hexanediethyl ether, gradually increasing the ether content from 1 to 5% byvolume. The less polar erythro isomer d,lerythro-trans,trans-2,4,6-trimethyl-5-methoxyocta-2,6-dienoic acid ethylester was obtained followed by a mixture of the diastereoisomers andfinally by the more polar threo isomerd,l-threo-trans,trans-2,4,6-trimethyl-5- methoxyocta-2,6-dienoic acidethyl ester. The erythro isomer had a B.P. 60-65 C. (0.1 mm. Hg) and thethreo isomer d,l-threo-trans,trans 2,4,6trimethyl-S-methoxyocta-2,6-dienoic acid ethyl ester had a B.P. -140 C.10 mm. Hg).

EXAMPLE 6 In a 500 ml. flask equipped with a condenser, dropping funneland magnetic stirrer, and protected by an inert atmosphere, 200 ml. ofanhydrous diethyl ether and 24 ml. of a 70% by weight solution of sodiumbis-(2- methoxyethoxy)-aluminum hydride in benzene were placed. Themixture was cooled in an ice-bath and 11.5 g. (0.048 mole) of erythroester i.e., d,l-erythro-trans,trans- 2,4,6-trimethyl 5methoxyocta-2,6-dienoic acid ethyl ester, in 10 ml. of diethyl ether wasadded dropwise. After the addition was complete, the reaction mixturewas stirred at 0 C. for 3 hours. Then a 20% by weight aqueous solutionof sodium hydroxide was added and the organic phase was separated. Theaqueous layer was extracted three times with dieth l ether. The combinedorganic solution was washed with water and dried with anhydrous sodiumsulfate. Evaporation of the solvent afforded the crude erythro isomerd,l-erythro-trans,trans- 2,4,6 trimethyl-5-methoxyocta-2,6-dien-l-ol,which was used without further purification for preparation of thecorresponding bromide. A pure sample was distilled at 140-150 C. (oilbath temperature) and 10 mm. Hg.

EXAMPLE 7 By the procedure of Example 6, 8.0 g. (0.033 mole) of thethreo ester i.e., d,l-threo-trans,trans-2,4,6-trimethyl-5-methoxyocta-2,6-dienoic acid ethyl ester, was converted to 6.5 g. ofcrude d,l-threo-trans,trans-2,4,6-trimethyl-5-methoxyocta-2,6-dien-1-ol. A pure sample was distilled at 140-150 C.(oil bath temperature) and 10 mm. Hg.

EXAMPLE 8 The erythro alcohol,d,l-erythro-trans,trans-2,4,6-triinethyl-S-methoxyocta-Z,6-dien-1-ol(4.0 g., 0.02 mole) in 24 ml. of anhydrous diethyl ether was placed in a100 ml. flask equipped with a condenser, stirrer and nitrogen inlet. Themixture was cooled to 20 C. in a Dry Ice acetone bath and 0.3 ml. ofanhydrous pyridine was added. A solution of 2.0 g. (7.4 mmoles) offreshly distilled phosphorus tribromide in 8 ml. of anhydrous diethylether was added dropwise with stirring over a 30-minute period. Afterthe addition was complete, the reaction mixture was stirred withoutcooling for 2 hours. The mixture was poured into ice water and thediethyl ether phase was separated. The aqueous phase was extracted threetimes with diethyl ether and the combined ether extracts were washedthree time with saturated aqueous sodium bicarbonate solution and thenwith water and dried with anhydrous sodium sulfate. Evaporation of thesolvent afforded crude erythro bromide, d,l-erythro-trans,trans-1-bromo-2,4,6-trimethyl-5-methoxyocta-2,6 diene. A pure sample wasdistilled at 60-70 C. (oil bath temperature) and 0.1 mm. Hg.

EXAMPLE 9 The threo alcohol, d,l-trans,trans 2,4,6 trimethyl-S-methoxyocta-2,6-dien-1-ol, (4.0 g., 0.02 mole) was con-v verted asdescribed in Example 8 to the crude threo bromide d,l threotrans,trans-1-bromo-2,4,6-trimethyl-5- methoxyocta-2,6-diene. Afterdistillation at 60-70" C. (oil bath temperature) and 0.1 mm. Hg, a puresample was obtained.

EXAMPLE 10 In a 100 ml. flask equipped with a magnetic stirrer,condenser and thermometer, and protected by an argon atmosphere, asolution of 4.36 g. (24.0 mole) of trans-3- methyl-2-penten-4-yn-1-oltetrahydropyranyl ether in 20 ml. of dry tetrahydrofuran (freshlydistilled from lithium aluminum hydride) was placed. The mixture wascooled to C. in an ice bath and methyl lithium (14.0 ml. of a 1.75 Msolution in diethyl ether, 24.5 mmoles) was added. The reaction mixturewas allowed to come to room temperature, stirred for 30 minutes, thenwas cooled to 0 C. Copper (I) chloride (50 mg.) was added, followed byaddition of a solution of the erythro bromide, d,lerythro-trans,trans 1bromo 2,4,6 trimethyl-S-methoxyocta-2,6-diene, (4.0 g., 15.4 mmoles) in16 ml. of dry tetrahydrofuran. The mixture was heated to the reflux for2 hours and then allowed to stir at room temperature overnight. Thereaction mixture was worked up by pouring onto water and ice andextracting the aqueous phase with diethyl ether. The combined organicphase was washed with aqueous saturated sodium chloride and dried withany hydrous sodium sulfate. Evaporation of the solvent afforded 6.7 g.of crude erythro isomer, d,l-erythro-trans, trans,trans 2 (3,7,9,11tetramethyl 10 methoxy- 2,7,1l tridecatrien 4 ynyl oxy) tetrahydropyran,which was purified by chromatography on silica gel (250 g. and elutionwith hexane containing increasing amounts of ether. This erythro isomerwas eluted with 95:5 parts by volume hexane: diethyl ether. This isomerwas obtained in pure form by distillation at 160-170 C. (oil bathtemperature) and 0.1 mm. Hg.

EXAMPLE 11 The threo bromide, i.e., d,l-threo-trans,trans-l-bromo-2,4,6-trimethyl-S-methoxyocta 2,6 diene (4.0 g., 15.4 mmoles) wasconverted by the procedure of Example 10 to give the threo isomer i.e.,d,l-threo-trans,trans,trans-2- (3,7,9,11-tetramethyl 10 methoxy 2,7,11tridecatrien 4 ynyl oxy)-tetrahydropyran. This isomer dis tilled at160-170 C. (oil bath temperature) and 0.1 mm. Hg.

EXAMPLE 12 The erythro tetrahydropyranyl ether, i.e.,d,l-erythrotrans,trans,trans 2 (3,7,9,1l-tetramethyl-lO-methoxy-2,7,11-tridecatrien 4 ynyl oxy)-tetrahyropyran (6.0 g. 16.6 mmoles) inml. of ethanol was stirred at 45-50 C. with 0.5 ml. of 1 N hydrochloricacid solution for 5 hours and then at room temperature overnight. Themixture was neutralized with solid sodium carbonate, filtered and thefiltrate was concentrated. The residue was dissolved in diethyl ether,Washed with saturated sodium chloride solution and dried with anhydroussodium sulfate. Evaporation of the solvent afforded d,l-erythro-trans,trans,trans 3,7,9,11tetramethyl-10-methoxy-2,7,1l-tridecatrien-4-yn-1-ol. This alcohol wasdissolved in 50 ml. of methylene chloride and added to a cooled (0 C.)suspension of 31.0 g. of activated manganese dioxide in 350 ml. ofmethylene chloride. The oxidation was carried out in a nitrogenatmosphere. The mixture was stirred .for one hour at 0 C. and for 1 hourat room temperature, then filtered and the filtrate was concentrated togive d,lerythro-trans,trans,trans 3,7,9,11 tetramethyl 10- methoxy2,7,11 tridecatrien 4 yn-l-al. This aldehyde in 60 ml. of ethanol wascombined with a solution of 7.5 g. of silver nitrate in 15 ml. of waterin a 250 ml. flask and the mixture was cooled to 0 C. A solution of 7.5g. of sodium hydroxide in 80 ml. of water was added dropwise withstirring. The reaction mixture was stirred at 0 C. for one hour, thenfor an additional hour at room temperature, and filtered. The filtratewas concentrated, the residue was dissolved in water and extracted withdiethyl ether. The aqueous phase was made acidic (pH 1) with 6 N aqueoushydrochloric acid and extracted three times with diethyl ether. Theselatter ether extracts were washed with a saturated aqueous sodiumchloride solution and dried with sodium sulfate. Evaporation of thesolvent afiForded d,l erythro trans,trans,trans 3,7,9,11-tetramethyl 10methoxytrideca 2,7,11 trien-4-ynoic acid. This acid which was dissolvedin 60 ml. of anhydrous ether was treated with a 1% solution ofdiazomethane in ether. The reaction mixture was stirred for one hour,then 5 ml. of dilute acetic acid was added and the aqueous phase wasextracted with diethyl ether. The combined organic phase was washedsuccessively with saturated sodium bicarbonate solution and water anddried with sodium fate. Evaporation of the solvent affordedd,l-erythro-trans, trans,trans-3,7,9,11 tetramethyl 10methoxytrideca-2,7, 11-trien-4-ynoic acid methyl ester, which waspurified by chromatography on g. of silica gel. Elution with hexanecontaining 2-3% b volume of diethyl ether afforded d,l erythrotrans,trans,trans 3,7,9,11-tetramethyl-10 methoxytrideca 2,7,11trien-4-ynoic acid methyl ester, which had a B.P. 140 C. (0.1 mm. Hg.)(oil bath temperature) EXAMPLE 13 The threo ether,d,l-threo-trans,trans,trans-2-(3,7,9,11- tetramethyl 10 methoxy 2,7,11tridecatrien-4-ynyloxy)-tetrahydropyran (5.65 g., 15.7 mmoles) wasconvertegigy the procedure of Example 12 to the threo ester, d,l re oflransdransflrans 3,7,9,11 tetramethyl-10- methoxytrideca 2,7,11 trien 4ynoic acid methyl ester obtained by elution of the silica gel columnwith hexane containing 3-4% by volume ether. The product had a B.P.

15 120-130" C. (0.05 mm.) (oil bath temperature). In this process, thefollowing compounds were .formed as intermediates:

d,l-threo-trans,trans,trans-3 ,7,9, 1 l-tetramethyllmethoxy-2,7,l1-tridecatrien-4-yn-l-ol;

d,l-threo-trans,trans,trans-3,7,9,1 l-tetramcthyl-lO- methoxy-2,7,11-tridecatrien-4-yn-1-al; and

d,l-threo-trans,trans,trans-3,7,9,1 l-tetramethyll0- methoxytrideca-2,7,1 l-trien-4-ynoic acid.

EXAMPLE 14 The erythro tetrahydropyranyl ether, i.e.,d,l-erythrotrans,trans,trans-2-(3,7,9,l1 tetramethyl methoxy- 2,7,11tridecatrien 4 ynyl-oxy)-tetrahydropyran, 2.88 g., 8 mmoles) in 172 ml.of heptane containing 0.8 g. of Lindlars catalyst and 2 ml. of quinolinewas stirred with hydrogen at atmospheric pressure until 115% of thetheoretical amount of hydrogen had been absorbed. After filtration, thesolution was concentrated and purified by chromatography on 700 g. ofneutral alumina (activity 11). Elution with hexane-benzene (3:1 parts byvolume) afforded d,l erythro trans,cis,trans,trans 2 (3,7,9,l1-tetramethyl 10 methoxy trideca 2,4,7,11-tetraenvloxy) tetrahydropyran.

EXAMPLE 15 By the procedure of Example 12, d,l-erythro-trans,cis,trans,trans 2 (3,7,9,1l-tetramethyl-l0-methoxy-2,4,7,11-tridecatetraenyloxy)-tetrahydropyran was first hydrolyzed tod,l-erythro-trans,cis,trans,trans-3,7,9, l l-tetramethyl-IO-methoxy-2,4,7,ll-tridecatetraen-2-ol which was then oxidized withmanganese dioxide to d,l-erythro-trans,cis,trans, trans 3,7,9,l1tetramethyl-10-methoxy-trideca-2,4,7,lltetraen-l-al. This aldehyde wasthen oxidized with silver oxide to the acid,d,l-erythro-trans,cis,trans,trans-3,7,9,l1- tetramethyl 10methoxy-trideca-2,4,7,ll-tetraenoic acid. This acid, uponrecrystallization from pentane was in the form of a colorless crystal(M.P. 6567 C.).

EXAMPLE 16 The erythro acid, d,l-erythro-trans,cis,trans,trans-3,7,9, 11tetramethyl 10 methoxy-trideca-2,4,7,1l-tetraenoic acid, (550 mg, 1.88mmoles) in diethyl ether solution was esterified by the procedure givenin Example 12 utilizing a 1% by weight solution of diazomethane indiethyl ether. The reaction product was distilled at 110-120 C. (oilbath temperature) and 0.05 mm. Hg to give d,l-erythro-trans,cis,trans,trans 3,7,9,1l-tetramethyl-10-methoxy-trideca-2,4,7,11-tetracnoic acid methyl ester.

EXAMPLE 17 The compoundd,l-threo-trans,trans,trans-2-(3,7,9,lltetramethyl10-methoxy-2,7,11-tridecatrien-4-ynyl-oxy)- tetrahydropyran (4.53 g.,12.6 mmoles) dissolved in heptane was hydrogenated by the proceduregiven in Example 14 utilizing 1.26 grams of Lindlar catalyst and 3.65ml. of quinoline to produce d,l-threo-trans,cis,trans,trans-2-(3,7, 9,11tetramethyl l0-methoxy-2-,4,7,l l-tridecatetraenyloxy)-tetrahydropyran.This compound was obtained after chromatographic purification andsubjected to hydrolysis by the procedure given in Example 12 to producethe alcohol, d,l-threo-trans,cis,trans,trans-3,7,9,1l-tetramethyl-lO-methoxy-trideca-2,4,7,l1-tetraen-l-ol. The alcohol was oxidized withmanganese dioxide by the procedure given in Example 12 to produce thealdehyde, d,l-threo-trans,cis, trans,trans3,7,9,1l-tetramethyl-l0-methoxytrideca-2,4,7, ll-tetraen-l-al. Thisaldehyde was oxidized with silver oxide by the procedure given inExample 12 to produce d,l threo trans,cis,trans,trans 3,7,9,l1tetramethyl-lO- methoxytrideca-2,4,7,l l-tetraenoic acid which wasdirectly converted without isolation by the procedure of Example 12 tothe ester, d,l-threo-trans,cis,trans,trans-3,7,9,1ltetramethyl 10methoxytrideca 2,4,7, 1 l-tetraenoic acid methyl ester. This ester waschromatographed on silica gel and eluted with hexane containing 3% byvolume of 16 diethyl ether. Distillation at C. to C. (oil bathtemperature) and 0.05 mm. Hg afforded pure ester.

EXAMPLE 18 2-ethynyl-2-methyl-1,3-dioxlane 3-butyn-2-one (13.6 g., 0.2mole), 37.4 g. (0.6 mole) of ethylene glycol, 90 mg. of p-toluenesulfonic acid and 45 mg. of hydroquinone in 90 ml. of pentane wereheated to reflux overnight. The organic layer was separated and theaqueous phase was extracted with diethyl ether. The combined organicphase was washed with saturated aqueous sodium chloride and dried withsodium sulfate. The solvent was removed by distillation and the residuewas distilled at 80-82 C. mm. Hg) to give 2-ethynyl-2-methyl-1,3-dioxolane.

. EXAMPLE 19 To a solution 12.3 g. (0.11 mole) of 2-ethynyl-2-methyl-1,3-dioxolane in 100 ml. of dry tetrahydrofuran in a 500 ml.,three-necked flask, fitted with a magnetic stirrer, condenser andprotected by a nitrogen atmosphere and cooled in an ice-bath, 42 ml.(0.10 mole) of a 2.4 molar solution of methyl lithium in diethyl etherwas added dropwise. After the addition was complete, the mixture wasstirred at 0 C. for another hour. Cuprous chloride (280 mg.) was addedin one portion followed by dropwise addition at 0 C. of a solution of17.3 g. (0.066 mole) of erythro bromided,l-erythro-trans,trans-1-bromo-2,4,6-trimethyl-5-methoxyocta-2,6-dienein 100 ml. of dry tetrahydrofuran. After the addition was complete, thereaction mixture was stirred at 0 C. for one hour, then heated to refluxfor 3 hours and then stirred at room temperature overnight. The mixturewas poured into ice water and extracted with diethyl ether. The combinedorganic extract was washed with saturated aqueous sodium chloridesolution and dried with sodium sulfate. Evaporation of the solventafforded d,l-erythro-trans,trans-2-methyl-2-[4,6,8- trimethyl7-methoxy-deca-4,8-dien-l-ynyl]-l,3-dioxolane, which was purified bychromatography on 500 g. of silica gel. Elution with hexane containing1-6% by volume of diethyl ether affordedd,l-erythro-trans,trans-2-methyl-2- [4,6,8trimethyl-7-methoxy-deca-4,8,-dien-1-ynyl]-1,3-dioxolane.

EXAMPLE 20 By the procedure of Example 19, d,l-threo-trans,trans- 1bromo 2,4,6 trimethyl-5-methoxyocta-2,6-diene was converted tod,l-threo-trans-trans-2-methyl-2-[4,6,8-trimethyl-7-methoxy-deca-4,8-dien-1-ynyl] -1,3-dioxolane.

EXAMPLE 21 A solution of the acetylenic ketal d,l-erythro-trans, trans 2methyl-2-[4,6,8-trimethyl-7-methoxy-deca-4,8- dien-l-ynyl]-l,3-dioxolane(4.25 g., 14.6 mmoles) in 40 ml. of methanol was hydrolyzed with 2T0 m1.of 3 N aqueous sulfuric acid. The mixture was stirred for 4 hours atroom temperature and then neutralized with solid sodium carbonate. Themixture was filtered and the filtrate was concentrated and thenredissolved in 50 ml. of diethyl ether. The ether solution was washedwith saturated aqueous sodium chloride solution, dried with sodiumsulfate and the solvent was evaporated to give the ketone,d,l-erythro-trans,trans-6,8,10-trimethyl-9-methoxydodeca-6,10-dien-3-yn-2-one.

Without further purification, the ketone was dissolved in 20 ml. of drytetrahydrofuran and was added dropwise to a suspension of 0.95 g. (2.5mmoles) of lithium aluminum hydride in ml. of tetrahydrofuran, which wascooled in an ice-bath and protected by a nitrogen atmosphere. After theaddition was complete, the mixture was heated to reflux for 2 hours.After reaction of the excess hydride with ethyl acetate, saturatedaqueous sodium sulfate solution was added. The mixture was filtered andthe residue was washed with diethyl ether; the combined filtrate wasdried with sodium sulfate. Evaporation of the 17 solvent aiforded thealcohol d,l-erythro-trans,trans,trans- 6,8,10trimethyl-9emethoxy-dodeca-3,6,10-trien-2-ol. A sample was distilled at100.110 C. (oil bath temperature) and 0.025 mm. Hg.

EXAMPLE; 22

EXAMPLE 23 The alcohol d,l erythro trans,trans,trans-6,8,IO-trimethyl-9-meth'oxy-dodeca 3,6,10 trien-Z-ol (3.2 g., 12 mmoles) and 28.0g. (0.32 mole) of activated manganese dioxide in 275 ml. of methylenechloride was stirred for 12 hours at room temperature in a nitrogenatmosphere. After filtration, the filtrate was concentrated to gived,lerythro-trans,trans,trans-6,8,10 trimethyl 9methoxydodeca-3,6,10-trien 2 one as product. The product was purified bychromatography on 75 g. silica gel and elution with hexane containing1-5% by volume diethyl ether to give of pure erythro c p-unsaturatedketone d,l-erythrotrans,trans,trans 6,8,10trimethyl-9-methoxydodeca-3,6, -trien-2-one. A sample, distilled at100-110 C. (oil bath temperature) and 0.1 mm. Hg.

EXAMPLE 24 In a 50 ml. flask equipped with a stirrer and protected by anatmosphere of nitrogen, 230 mg. (1 mmole) ofd,lerythro-trans,-trans,trans-6,8,1'0 trimethyl 9methoxydodeca-3,6,10-trien-2-one, and 265 mg. (1.45 mmoles) oftrimethyl-phosphonoacetate were dissolved in 4 ml. of dry 'benzene andcooled to C. in an ice bath. A solution of freshly prepared sodiummethoxide, prepared by addition of 34.5 mg. (1.5 mmole) of sodium metalto 2 ml; of methanol, was thenadded slowly. After the" additionwascomplete, the reaction mixture was stirred at room temperature for 3hours, then poured into ice Water and extracted'with benzene. Thebenzene extract was washed with saturated'sodium chloride solution,dried with sodium sulfate and evaporated. The crude product was purifiedby chromatography on 10 g. of silica gel. Elution with hexane containing1-5% by volume of .diethyl ether afforded d,lerythro-all-trans,3,7,9,l1-tetramethyl-10methoxy-trideca-2,4,7,1l-tetraenoic acid methyl ester.

EXAMPLE In a 100 ml. three-necked flask fitted with a magnetic stirrerand protected by a nitrogen atmosphere, 345 mg. (8.5 mg. (8.5 mmoles) ofsodiumhydride (59.2%by weight mineral oil dispersion) was .Washed freeof the mineral oil with pentane and the resulting oil-free hydride wassuspended in 6 ml. of dry tetrahydrofuran and cooled to 0 C. in anice-bath. A solution-of 2.23 g. (8.5 mmoles) of diethyl-Z-(cyclohexylamino) vinylphosphonate in 15 ml. of tetrahydrofuran wasadded dropwise at 0 C. over a 15-minute period. The mixture was furtherstirred for minutes at this temperature. The mixture was then cooled to-40 C. and a solution of 2.15 g. (8.65 mmoles) ofd,l-erythro-trans,trans,trans6,8,IO-trimethyl-9-methoxydodeca-3,6,10-trien-2-one in 21 m1. oftetrahydrofuran was added dropwise. The reaction mixture was allowed tocome slowly to 0 C. and maintained at this temperature for another hour.'Ihe' mixture was poured into ice water, saturated with sodium chlorideand extracted with diethyl ether. The organic extract was washed withsaturated aqueous sodium chloride solution, dried with sodium sulfateand concentrated to give 4.1g. of a residue, which was dissolved in 50ml. of benzene.

The benzene solution was treated with ml. of a 10% solution of oxalicacid and heated to the reflux for 2 hours under nitrogen. The organiclayer was separated, washed with saturated sodium chloride solution,dried and evaporated to gived,l-erythro-all-trans-3,7,9,1l-tetramethyll0l0-methoxy-trideca-2,4,7, 1l-tetraenl-al.

EXAMPLE 26 By the procedure of Example 12, d,l-erythro-all-trans-3,7,9,11-tetramethyl 10 methoxy-trideca-2,4,7,ll-tetraen-l-al wasoxidized with silver oxide to form the acid, d,lerythro-alltrans-3,7,9,ll-tetramethyl-IO-methoxy-trideca-2,4,7,11-tetraenoicacid. This acid was then reacted with diazomethane in the mannerdescribed in Example 12 to produce d,lerythro-all-trans-3,7,9,1l-tetramethyll0-methoxy-trideca-2,4,7,ll-tetraenoicacid methyl ester.

EXAMPLE 27 By the procedure of Example 24, d,l-threo-all-trans-6,8,10-trimethyl-9-methoxy-dodeca-3,6,IO-trien 2 one was reacted withtrimethyl phosphonoacetate to produced,lthreo-all-trans-3,7,9,ll-tetramethyl l0 methoxy-trideca-2,4,7,1l-tetraenoic acid methyl ester.

EXAMPLE 28 By the procedure of Example 25, d,l-threo-trans,trans,

trans-6,8,10-trimethyl-9-methoxy-dodeca 3,6,10 trien- 2-one was reactedwith 2 [cyclohexylamino]-vinylphosphonate to produce d,l threo alltrans-3,7,9,11-tetramethyll0-methoxy-trideca-2,4,7, 1 l-tetraen-l-al.

EXAMPLE 29 EXAMPLE 30 By the procedure of Example 23,d,l-threo-trans,trans, trans-6,18,10-trimethyl 9methoxy-dodeca-3,6,IO-trien- 2-ol was similarly oxidized to the threoketone, d,l-threotrans,trans,trans-6,8,10-trimethyl 9 methoxy-dodeca-3,6,10-trien-2-one.

EXAMPLE 31 18 g. (0.05 mole) of carbethoxyethylidenetriphenylphosphorane, 7.8 g. (0.05 mole) of2,4-dimethyl-3-methoxy-4-hexenal and 125 ml. of absolute ethanol wereheated to reflux for 48 hours in an inert atmosphere. The reactionmixture was allowed to cool, diluted with ether and poured into icewater. The organic phase was separated and the aqueous phase wasextracted twice with diethyl ether. The combined organic phase waswashed with saturated aqueous sodium chloride solution and dried withanhydrous sodium sulfate. Evaporation of the solvent gave a yellow solidwhich was triturated three times with pentane. Removal of the pentaneafiorded a mixture I 2,4,6 trimethyl-S-methoxyocta-2,6-dienoic acidethyl ester and d,l threo-cis, trans-2,4,6trimethyl-5-methoxyocta-2,6-dienoic acid ethyl ester.

EXAMPLE 32 By the procedure of Example 5, the mixture obtained inExample 31 is separated into the d,l-erythro-cis,trans-2,4,6-trimethyl-5-methoxyocta 2,6 dienoic acid ethyl ester andd,l-threo-cis,trans 2,4,6 trimethyl-S-methoxyocta-2,6-dienoic acid ethylester.

19 EXAMPLE 33 By the procedure of Examples 6, 8, 10 and 12, thed,lerythio-cis,trans 2,4,6 trimethyl-5-methoxy-2,6-dienoic acid ethylester was converted to d,l-erythro-trans,cistrans 3,7,9,l1 tetramethyl10 methoxytrideca-2,7,1ltrien-4-ynoic acid methyl ester via thefollowing intermediates:

d,l-erythro-cis,trans-2,4,6-trimethyl-S-methoxyocta- 2,6-dien- 1-01;

d,l-erythro-cis,trans-1-bromo-2,4,6-trimethyl-5- methoxyocta-2,6-diene;

d,l-erythro-trans,cis,trans-2- 3,7 ,9,1 l-tetramethyl-IO-methoxy-2,7,11-tridecatrien-4-ynyl-oxy)- tetrahydropyran;

d,lerythro-trans,cis,trans-3,7,9,l1-tetramethyl-10- methoxy-2,7,11-tridecatrien-4-yn- 1-01;

d,l-erythro-trans,cis,trans-3,7,9,1 l-tetramethyl- 10- methoXy-2,7,11-tridecatrien-4-yn-l -al; and

d,l-erythro-trans,cis,trans-3,7,9,1l-tetramethyllmethoxy-2,7,11-tridecatrien-4-ynoic acid.

EMMPLE 34 By the procedure of Examples 14, 15 and 16, d,lerythrotrans,cis,trans 2 (3,7,9,11 tetramethyl 10- methoxy 2,7,11 tridecatrien4 ynyl-oxy)-tetrahydropyran is converted tod,l-erythro-trans,cis,cis,trans-3,7,9, 11 tetramethyl 10methoxy-trideca-2,4,7,1l-tetraenoic acid methyl ester via the followingintermediates:

d,l-erythro-trans,cis,cis, trans-2- (3,7,9,1 l-tetramethyl-10-methoxy-trideca-2,4,7,1 1-tetraenyl-oxy)- tetrahydropyran;d,l-erythro-trans,cis,cis,trans-3,7,9,1 l-tetramethyl-IO- methoxy-2,4,7,1 l-tridecatetraen- 1-01; d,l-erythro-trans,cis,cis,trans-3,7,9, ll-tetramethyl-IO methoxy-2,4,7,1 l-tridecatetraenl-al; andd,l-erythro-trans,cis,cisMans-3,7,9, 1 l-tetramethyl-IO methoxy-2,4,7,1l-tridecatetraenoic acid.

EXAMPLE 35 By the procedure of Examples 6, 8, 10 and 12, thed,lthreo-cis,trans-2,4,6-trimethyl--methoxy-2,6-dienoic acid ethyl esterwas converted to d,l-threo-trans,cis,trans-3,7,9, ll-tetramethylmethoxytrideca-2,7,11-trien-4-ynoic acid methyl ester via the followingintermediates:

EXAMPLE 36 By the procedure of Example 14, 15 and 16, d,l-threoetrans,cis,trans 2 (3,7,9,1l-tetramethyl-10-methoxy-2,7,1l-trideca-trien-4-ynyl-oxy)-tetrahydropyran is converted to d,l threotrans,cis,cis,trans 3,7,9,11-tetramethyl-10-methoxy-trideca-2,4,7,1l-tetraenoic acid methyl ester via the followingintermediates: d,l-threo-trans,cis,cis,trans-2- 3,7,9, 1 l-tetramethyl-10- methoxy-trideca-2,4,7,11-tetraeny1-oxy)- tetrahydropyran;

d,l-threo-trans,cis,cis,trans-3,7,9,1 l-tetramethyl-l 0- methoxy-2,4,7,1l-tridecatetraen-l-ol;

d,l-threo-trans,cis,cis,tran-3,7,9, 1 l-tetramethyl-10- 20methoxy-2,4,7,1l-tridecatetraen-l-al; andd,l-threo-trans,cis,cis,trans-3,7,9, 1 l-tetramethyl-IO-methoxy-2,4,7,ll-tridecatetraenoic acid.

We claim: 1. A compound of the formula:

wherein R is hydrogen or lower alkyl and A and B are individuallyhydrogen or taken together form a carbon to carbon bond and R is loweralkyl or benzyl.

2. The compound of claim 1 wherein A and B taken together form a carbonto carbon bond.

3. The compound of claim 2 wherein said compound is d,l erythrotrans,trans,trans 3,7,9,11 tetrarnethyl-IO-methoxytrideca-2,7,11-trien-4-ynoic acid.

4. The compound of claim 2- wherein said compound is d,lerythrotrans,trans,trans 3,7,9,11 tetramethyl-IO- methoxytrideca-2,7,ll-trien-4-ynoic acid methyl ester.

5. The compound of claim 2 wherein said compound is d,l threotrans,trans,trans 3,7,9,11 tetramethyl 10- methoxytrideca-2,7,1l-trien-4-ynoic acid.

6. The compound of claim 2 wherein said compound is d,l threotrans,trans,trans 3,7,9,11 tetramethyl 10- methoxytrideca-2,7,11-trien-4-ynoic acid methyl ester.

7. The compound of claim 1 wherein A and B are hydrogen with the doublebond formed thereby having a cis configuration.

8. The compound of claim 7 wherein said compound is d,l-erythrotrans,cis,trans,trans 3,7,9,11 tetramethyll0-methoxytrideca-2,4,7,1l-tetraenoic acid.

-9. The compound of claim 7 wherein said compound isd,l-erythro-trans,cis,trans,trans 3,7,9,11 tetramethyl-10-methoxytrideca-2,4,7,1l-tetraenoic acid methyl ester.

10. The compound of claim 7 wherein said compound isd,l-threo-trans,cis,trans,trans 3,7,9,l1 tetramethyl-lO-methoxytrideca-2,4,7,ll-tetraenoic acid.

11. The compound of claim 7 wherein said compoundisd,l-threo-trans,cis,trans,trans 3,7,9,l1 tetramethyl-IO-methoxytrideca-2,4,7,1l-tetraenoic acid methyl ester.

12. The compoundxof claim 1 wherein A and B are hydrogen forming adouble bond having a trans configuration.

13. The compound of claim 12 wherein said compound is d,l-erythroall-trans-3,7,9,l1-tetramethyl-IO-methoxytrideca-2,4,7,1l-tetraenoicacid. 7

14. The compound of claim 12 wherein said compound is d,l-erythro alltrans-3,7,9,1l-tetramethyl-l0-methoxy-' trideca-2,4,7,1l-tetraenoic acidmethyl ester.

15. The compound of claim 12 wherein said compound is d,l-threo alltrans-3,7,9,l1-tetramethyl-10-methoxytrideca-2,4,7,11tetraenoic acidmethyl ester.

r 16. .T he compound of claim 12 wherein said compound is'-d,l-threoalltrans3,7,9,ll-tetramethyl-lO-methoxytrideca-2,4,7,1l-tetraenoic acid.

References Cited UNITED STATES PATENTS 5/1973 Henrick et al 260465.91/1972 Jarolim at al 260240 R 260413, 340.9, 345.9, 594 R, 602, 614 R,615 A, 615 R; 424312, 318, Dig. 12

